This application is a continuation of International application No. PCT/FR99/02,753, filed Nov. 09, 1999; which claims the benefit of priority of French Patent Application No. 98/14,250, filed Nov. 13, 1998.
The present invention relates to the combination of xcex1-tocopherol and of riluzole or of a pharmaceutically acceptable salt of this compound and the use of this combination for the treatment of amyotrophic lateral sclerosis (ALS).
Amyotrophic lateral sclerosis, also known by the name of CHARCOT""s disease and LOU GEHRIG""s disease, was described for the first time by CHARCOT in 1865. ALS is a fatal disease resulting from degeneration of the motoneurons. The disease is accompanied by progressive paralysis, leading to the loss of motor and respiratory functions and then to death within a period of two to eight years after the appearance of the first symptoms.
To date, only riluzole (2-amino-6-trifluoromethoxybenzothiazole) is marketed under the name RILUTEK(copyright) for the treatment of amyotrophic lateral sclerosis. Riluzole makes it possible mainly to slow down the progression of the disease.
It has now been found that the combination of riluzole or one of its pharmaceutically acceptable salts and of xcex1-tocopherol (vitamin E) makes it possible to slow down the disease more substantially than riluzole alone and also to reduce fatigue in patients and the plasma concentration of malondialdehyde.
The study was carried out in 289 patients in total aged over 18 years, who have been suffering from ALS for less than 5 years and in whom the vital capacity/theoretical normal vital capacity ratio is greater than or equal to 60% (the vital capacity is a routine conventional measurement of the respiratory function also called lung function test).
The patients are divided into 2 groups:
group 1: 145 patients treated with 100 mg/day of riluzole by the oral route and 1000 mg/day of xcex1-tocopherol by the oral route,
group 2: 144 patients treated with 100 mg/day of riluzole by the oral route and placebo.
Some patients in the 2 groups no longer meeting, in a second evaluation, the inclusion criteria or who had not followed the treatment correctly, were not taken into account for the determination of the results.
The patients are monitored for a year. The results are measured on functional scales (Munsat""s functional states (RIVIERE et al., Arch. Neurol., 55, 526 (1998)), a visual analog scale (VAS) for fatigability (LACOBLEZ et al., The Lancet, 347, 1425 (1996); BENSIMON et al., New England Journal of Medicine, 330, 585 (1994)) and plasma concentration of malondialdehyde, a biochemical marker for oxidative stress (FAVIER, Analysis of free radicals in biological systems, Birk Hauser, Basel/Switzerland, 1995 p. 100-117).